US10501515B2ActiveUtilityA1
Hepcidin analogues and uses thereof
Assignee: PROTAGONIST THERAPEUTICS INCPriority: Mar 15, 2013Filed: Feb 28, 2019Granted: Dec 10, 2019
Est. expiryMar 15, 2033(~6.7 yrs left)· nominal 20-yr term from priority
Inventors:Mark Leslie SmytheGregory Thomas BourneSimone VinkBrian Troy FrederickPraveen MadalaAnne Pernille Tofteng SheltonJacob Ulrik Fog
A61P 3/12A61P 3/00A61K 38/00C07K 14/575
95
PatentIndex Score
18
Cited by
295
References
30
Claims
Abstract
The present invention relates, inter alia, to certain hepcidin peptide analogues, including peptides and dimers thereof, and to the use of the peptides and peptide dimers in the treatment and/or prevention of a variety of diseases, conditions or disorders, including treatment and/or prevention of iron overload diseases, which include hereditary hemochromatosis and iron-loading anemias, and other conditions and disorders described herein.
Claims
exact text as granted — not AI-modifiedThe invention claimed is:
1. A method of treating a disease of iron metabolism in a subject, comprising administering to the subject an effective amount of at least one peptide according to formula I′:
(I′)
(SEQ ID NO: 21)
R1′-X′-Y′-R2′
or a pharmaceutically acceptable salt thereof, wherein
R1′ is hydrogen, a C1-C6 alkyl, a C6-C12 aryl, a C1-C20 alkanoyl or pGlu;
R2′ is —NH 2 or —OH;
X′ is a peptide sequence having the formula Ia′
(Ia′)
(SEQ ID NO: 13)
X1-X2-X3-X4-X5-X6-X7-X8-X9-X10
wherein
X1 is Asp, Ida, pGlu, bhAsp, or absent;
X2 is Thr;
X3 is His;
X4 is Phe, or Dpa;
X5 is Pro, or bhPro;
X6 is Ile, Cys, or Arg;
X7 is Cys, IIe, Leu, or Val;
X8 is Ile, Arg, Phe, Gln, Lys, or Glu;
X9 is Phe or bhPhe; and
X10 is Lys, Phe or absent;
wherein if Y′ is absent, X7 is Ile; and
Y′ is a peptide sequence having the formula IIa′
(IIa′)
(SEQ ID NO: 16)
Y1-Y2-Y3-Y4-Y5-Y6-Y7-Y8-Y9-Y10-Y11-Y12-Y13-Y14-Y15
wherein
Y1 is Gly, Cys, Ala, Phe, Pro, Glu, Lys, D-Pro, Val, Ser or absent;
Y2 is Pro, Ala, Cys, Gly or absent;
Y3 is Arg, Lys, Pro, Gly, His, Ala, Trp or absent;
Y4 is Ser, Arg, Gly, Trp, Ala, His, Tyr or absent;
Y5 is Lys, Met, Arg, Ala or absent;
Y6 is Gly, Ser, Lys, IIe, Ala, Pro, Val or absent;
Y7 is Trp, Lys, Gly, Ala, IIe, Val or absent;
Y8 is Val, Thr, Gly, Cys, Met, Tyr, Ala, Glu, Lys, Asp, Arg or absent;
Y9 is Cys, Tyr or absent;
Y10 is Met, Lys, Arg, Tyr or absent;
Y11 is Arg, Met, Cys, Lys or absent;
Y12 is Arg, Lys, Ala or absent;
Y13 is Arg, Cys, Lys, Val or absent;
Y14 is Arg, Lys, Pro, Cys, Thr or absent; and
Y15 is Thr, Arg or absent;
wherein the peptide of formula I′ comprises two cysteine residues linked via a disulfide bond, wherein the peptide is optionally PEGylated on R1′, X′, or Y′;
wherein a side chain of an amino acid of the peptide is optionally conjugated to a lipophilic substituent or a polymeric moiety; and
wherein the disease of iron metabolism is hereditary hemochromatosis, iron hemochromatosis, HFE (human factors engineering) mutation hemochromatosis, hepcidin deficiency, transfusional iron overload, or thalassemia.
2. The method of claim 1 , wherein the peptide of Formula I′ is PEGylated on R1′, X′, or Y′, or wherein a side chain of an amino acid of the peptide of Formula I′ is conjugated to a lipophilic substituent or a polymeric moiety.
3. The method of claim 1 , wherein R1′ is hydrogen, isovaleric acid, isobutyric acid or acetyl.
4. The method of claim 1 , wherein X′ is a peptide sequence having formula Ib′
(Ib′)
(SEQ ID NO: 14)
X1-Thr-His-X4-X5-X6-X7-X8-Phe-X10
wherein
X1 is Asp, Ida, pGlu, bhAsp or absent;
X4 is Phe or Dpa;
X5 is Pro or bhPro;
X6 is Ile, Cys or Arg;
X7 is Cys, IIe, Leu or Val;
X8 is Ile, Lys, Glu, Phe, Gln or Arg; and
X10 is Lys or absent;
or having formula Ic′
(Ic′)
(SEQ ID NO: 15)
X1-Thr-His-X4-X5-Cys-I1e-X8-Phe-X10
wherein
X1 is Asp, Ida, pGlu, bhAsp or absent;
X4 is Phe or Dpa;
X5 is Pro or bhPro;
X8 is Ile, Lys, Glu, Phe, Gln or Arg; and
X10 is Lys or absent.
5. The method of claim 1 , wherein X1 is Asp, X4 is Phe, and X5 is Pro.
6. The method of claim 1 , wherein the peptide of Formula I′ comprises one of the following sequences:
(SEQ ID NO: 29)
DTHFPICIFGPRSKGWVC;
(SEQ ID NO: 38)
DTHFPCIIFGPRSKGWVCK;
(SEQ ID NO: 128)
DTHFPCIIFEPRSKGWVCK;
(SEQ ID NO: 164)
DTHFPCIIFGPRSKGWACK;
(SEQ ID NO: 168)
DTHFPCIIFGPRSKGWVCKK;
(SEQ ID NO: 57
DTHFPCIIFVCHRPKGCYRRVCR;
(SEQ ID NO: 125)
DTHFPCIKFGPRSKGWVCK;
(SEQ ID NO: 173)
DTHFPCIKFKPRSKGWVCK;
(SEQ ID NO: 106)
DTHFPCIIFGPRSRGWVCK;
(SEQ ID NO: 135)
DTHFPCIKFGPKSKGWVCK;
(SEQ ID NO: 207)
DTHFPCIKFEPRSKGCK;
(SEQ ID NO: 265)
DTHFPCIKFEPKSKGWECK;
(SEQ ID NO: 245)
DTHFPCIKFEPRSKKCK;
(SEQ ID NO: 247)
DTHFPCIKFEPRSKGCKK;
(SEQ ID NO: 249)
DTHFPCIKFKPRSKGCK;
or
(SEQ ID NO: 250)
DTHFPCIKFEPKSKGCK,
or a pharmaceutically acceptable salt thereof.
7. The method of claim 1 , wherein the peptide of Formula I′ comprises one of the following sequences:
(SEQ ID NO: 29)
Isovaleric acid-DTHFPICIFGPRSKGWVC-NH 2 ;
(SEQ ID NO: 38)
Isovaleric acid-DTHFPCIIFGPRSKGWVCK-NH 2 ;
(SEQ ID NO: 128)
Isovaleric acid-DTHFPCIIFEPRSKGWVCK-NH 2 ;
(SEQ ID NO: 164)
Isovaleric acid-DTHFPCIIFGPRSKGWACK-NH 2 ;
(SEQ ID NO: 168)
Isovaleric acid-DTHFPCIIFGPRSKGWVCKK-NH 2 ;
(SEQ ID NO: 57)
Isovaleric acid-DTHFPCIIFVCHRPKGCYRRVCR-NH 2 ;
(SEQ ID NO: 172)
Isovaleric acid-DTHFPCI(K(PEG8))FGPRSKGWVCK-NH 2 ;
(SEQ ID NO: 173)
Isovaleric acid-DTHFPCIKF(K(PEG8))PRSKGWVCK-NH 2 ;
(SEQ ID NO: 199)
Isovaleric acid-DTHFPICIFGPRS(K(PEG8))GWVCNH 2 ;
(SEQ ID NO: 200)
Isovaleric acid-DTHFPICIFGPRS(K(PEG4))GWVCNH 2 ;
(SEQ ID NO: 201)
Isovaleric acid-DTHFPCIIFGPRSRGWVC(K(PEG8))-NH 2 ;
(SEQ ID NO: 202)
Isovaleric acid-DTHFPCIIFGPRSRGWVC(K(PEG4))-NH 2 ;
(SEQ ID NO: 203)
Isovaleric acid-DTHFPCIIFGPRSRGWVC(K(PEG2))-NH 2 ;
(SEQ ID NO: 183)
Isovaleric acid-DTHFPCI(K(Palm))FGPRSKGWVCK-NH 2 ;
(SEQ ID NO: 217)
Isovaleric acid-DTHFPCIKF)K(Palm))PRSKGWVCK-NH 2 ;
(SEQ ID NO: 219)
Isovaleric acid-DTHFPCIKFGP(K(Palm))SKGWVCK-NH 2 ;
(SEQ ID NO: 220)
Isovaleric acid-DTHFPCIKFGPRS(K(Palm))GWVCK-NH2;
(SEQ ID NO: 221)
Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(Palm))-NH 2 ;
(SEQ ID NO: 222)
Isovaleric acid-DTHFPCI(K(PEG3-Palm))FGPRSKGWVCK-
NH 2 ;
(SEQ ID NO: 223)
Isovaleric acid-DTHFPCIKF(K(PEG3-Palm))PRSKGWVCK-
NH 2 ;
(SEQ ID NO: 224)
Isovaleric acid-DTHFPCIKFGP(K(PEG3-Palm))SKGWVCK-
NH 2 ;
(SEQ ID NO: 225)
Isovaleric acid-DTHFPCIKFGPRS(K(PEG3-Palm))GWVCK-
NH 2 ;
(SEQ ID NO: 226)
Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(PEG3-Palm))-
NH 2 ;
(SEQ ID NO: 176)
Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(PEG8))-NH 2 ;
(SEQ ID NO: 241)
Isovaleric acid-DTHFPCI(K(isoGlu-Palm))FEPRSKGCK-
NH 2 ;
(SEQ ID NO: 242)
Isovaleric acid-DTHFPCIKF-K(isoGlu-Palm)-PRSKGCK-
NH 2 ;
(SEQ ID NO: 243)
Isovaleric acid-DTHFPCIKFEP(K(isoGlu-Palm))SKGCK-
NH 2 ;
(SEQ ID NO: 265)
Isovaleric acid-DTHFPCIKFEP(K(isoGlu-Palm))SKGWECK-
NH 2 ;
(SEQ ID NO: 244)
Isovaleric acid-DTHFPCIKFEPRS(K(isoGlu-Palm))GCK-
NH 2 ;
(SEQ ID NO: 245)
Isovaleric acid-DTHFPCIKFEPRSK(K(isoGlu-Palm))CK-
NH 2 ;
(SEQ ID NO: 246)
Isovaleric acid-DTHFPCIKFEPRSKGCK(K(isoGlu-Palm))-
NH 2 ;
(SEQ ID NO: 248)
Isovaleric acid-DTHFPCI-K(Dapa-Palm)-FEPRSKGCK-NH 2 ;
(SEQ ID NO: 249)
Isovaleric acid-DTHFPCIK(F(Dapa-Palm))PRSKGCK-NH 2 ;
(SEQ ID NO: 250)
Isovaleric acid-DTHFPCIKFEP(K(Dapa-Palm))SKGCK-NH 2 ;
(SEQ ID NO: 251)
Isovaleric acid-DTHFPCIKFEPRS(K(Dapa-Palm))GCK-NH 2 ;
(SEQ ID NO: 252)
Isovaleric acid-DTHFPCIKFEPRSK(K(Dapa-Palm))CK-NH 2 ;
(SEQ ID NO: 253)
Isovaleric acid-DTIFPCIKFEPRSKGC(K(Dapa-Palm))K-
NH 2 ;
or
(SEQ ID NO: 254)
Isovaleric acid-DTHFPCIKFEPRSKGC(K(Dapa-Palm))-NH 2 ,
or a pharmaceutically acceptable salt thereof, wherein the peptide of Formula I′ comprises two cysteine residues linked via a disulphide bond.
8. The method of claim 1 , wherein the peptide of formula I′ comprises one of the following sequences:
(SEQ ID NO: 29)
DTHFPICIFGPRSKGWVC;
(SEQ ID NO: 38)
DTHFPCIIFGPRSKGWVCK;
(SEQ ID NO: 128)
DTHFPCIIFEPRSKGWVCK;
(SEQ ID NO: 164)
DTHFPCIIFGPRSKGWACK;
(SEQ ID NO: 168)
DTHFPCIIFGPRSKGWVCKK;
(SEQ ID NO: 57
DTHFPCIIFVCHRPKGCYRRVCR;
(SEQ ID NO: 125)
DTHFPCIKFGPRSKGWVCK;
(SEQ ID NO: 173)
DTHFPCIKFKPRSKGWVCK;
(SEQ ID NO: 106)
DTHFPCIIFGPRSRGWVCK;
(SEQ ID NO: 135)
DTHFPCIKFGPKSKGWVCK;
(SEQ ID NO: 207)
DTHFPCIKFEPRSKGCK;
(SEQ ID NO: 265)
DTHFPCIKFEPKSKGWECK;
(SEQ ID NO: 245)
DTHFPCIKFEPRSKKCK;
(SEQ ID NO: 247)
DTHFPCIKFEPRSKGCKK;
(SEQ ID NO: 249)
DTHFPCIKFKPRSKGCK;
or
(SEQ ID NO: 250)
DTHFPCIKFEPKSKGCK.
9. The method of claim 1 , wherein the peptide comprises one of the following sequences:
(SEQ ID NO: 29)
Isovaleric acid-DTHFPICIFGPRSKGWVC-NH 2 ;
(SEQ ID NO: 38)
Isovaleric acid-DTHFPCIIFGPRSKGWVCK-NH 2 ;
(SEQ ID NO: 128)
Isovaleric acid-DTHFPCIIFEPRSKGWVCK-NH 2 ;
(SEQ ID NO: 164)
Isovaleric acid-DTHFPCIIFGPRSKGWACK-NH 2 ;
(SEQ ID NO: 168)
Isovaleric acid-DTHFPCIIFGPRSKGWVCKK-NH 2 ;
(SEQ ID NO: 57)
Isovaleric acid-DTHFPCIIFVCHRPKGCYRRVCR-NH 2 ;
(SEQ ID NO: 172)
Isovaleric acid-DTHFPCI(K(PEG8))FGPRSKGWVCK-NH 2 ;
(SEQ ID NO: 173)
Isovaleric acid-DTHFPCIKF(K(PEG8))PRSKGWVCK-NH 2 ;
(SEQ ID NO: 199)
Isovaleric acid-DTHFPICIFGPRS(K(PEG8))GWVCNH 2 ;
(SEQ ID NO: 200)
Isovaleric acid-DTHFPICIFGPRS(K(PEG4))GWVCNH 2 ;
(SEQ ID NO: 201)
Isovaleric acid-DTHFPCIIFGPRSRGWVC(K(PEG8))-NH 2 ;
(SEQ ID NO: 202)
Isovaleric acid-DTHFPCIIFGPRSRGWVC(K(PEG4))-NH 2 ;
(SEQ ID NO: 203)
Isovaleric acid-DTHFPCIIFGPRSRGWVC(K(PEG2))-NH 2 ;
(SEQ ID NO: 183)
Isovaleric acid-DTHFPCI(K(Palm))FGPRSKGWVCK-NH 2 ;
(SEQ ID NO: 217)
Isovaleric acid-DTHFPCIKF)K(Palm))PRSKGWVCK-NH 2 ;
(SEQ ID NO: 219)
Isovaleric acid-DTHFPCIKFGP(K(Palm))SKGWVCK-NH 2 ;
(SEQ ID NO: 220)
Isovaleric acid-DTHFPCIKFGPRS(K(Palm))GWVCK-NH2;
(SEQ ID NO: 221)
Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(Palm))-NH 2 ;
(SEQ ID NO: 222)
Isovaleric acid-DTHFPCI(K(PEG3-Palm))FGPRSKGWVCK-
NH 2 ;
(SEQ ID NO: 223)
Isovaleric acid-DTHFPCIKF(K(PEG3-Palm))PRSKGWVCK-
NH 2 ;
(SEQ ID NO: 224)
Isovaleric acid-DTHFPCIKFGP(K(PEG3-Palm))SKGWVCK-
NH 2 ;
(SEQ ID NO: 225)
Isovaleric acid-DTHFPCIKFGPRS(K(PEG3-Palm))GWVCK-
NH 2 ;
(SEQ ID NO: 226)
Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(PEG3-Palm))-
NH 2 ;
(SEQ ID NO: 176)
Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(PEG8))-NH 2 ;
(SEQ ID NO: 241)
Isovaleric acid-DTHFPCI(K(isoGlu-Palm))FEPRSKGCK-
NH 2 ;
(SEQ ID NO: 242)
Isovaleric acid-DTHFPCIKF-K(isoGlu-Palm)-PRSKGCK-
NH 2 ;
(SEQ ID NO: 243)
Isovaleric acid-DTHFPCIKFEP(K(isoGlu-Palm))SKGCK-
NH 2 ;
(SEQ ID NO: 265)
Isovaleric acid-DTHFPCIKFEP(K(isoGlu-Palm))SKGWECK-
NH 2 ;
(SEQ ID NO: 244)
Isovaleric acid-DTHFPCIKFEPRS(K(isoGlu-Palm))GCK-
NH 2 ;
(SEQ ID NO: 245)
Isovaleric acid-DTHFPCIKFEPRSK(K(isoGlu-Palm))CK-
NH 2 ;
(SEQ ID NO: 246)
Isovaleric acid-DTHFPCIKFEPRSKGCK(K(isoGlu-Palm))-
NH 2 ;
(SEQ ID NO: 248)
Isovaleric acid-DTHFPCI-K(Dapa-Palm)-FEPRSKGCK-NH 2 ;
(SEQ ID NO: 249)
Isovaleric acid-DTHFPCIK(F(Dapa-Palm))PRSKGCK-NH 2 ;
(SEQ ID NO: 250)
Isovaleric acid-DTHFPCIKFEP(K(Dapa-Palm))SKGCK-NH 2 ;
(SEQ ID NO: 251)
Isovaleric acid-DTHFPCIKFEPRS(K(Dapa-Palm))GCK-NH 2 ;
(SEQ ID NO: 252)
Isovaleric acid-DTHFPCIKFEPRSK(K(Dapa-Palm))CK-NH 2 ;
(SEQ ID NO: 253)
Isovaleric acid-DTIFPCIKFEPRSKGC(K(Dapa-Palm))K-
NH 2 ;
or
(SEQ ID NO: 254)
Isovaleric acid-DTHFPCIKFEPRSKGC(K(Dapa-Palm))-NH 2 ,
10. The method of claim 1 , wherein the disease of iron metabolism is hereditary hemochromatosis, iron hemochromatosis, HFE (human factors engineering) mutation hemochromatosis, hepcidin deficiency, transfusional iron overload, or thalassemia.
11. The method of claim 1 , wherein the disease of iron metabolism is hereditary hemochromatosis (HH).
12. The method of claim 1 , wherein the disease of iron metabolism is a thalassemia, optionally thalassemia intermedia, alpha thalassemia, or β-thalassemia.
13. The method of claim 12 , wherein the disease of iron metabolism is β-thalassemia.
14. The method of claim 1 , wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCIIFGPRSKGWVCK-NH 2 (SEQ ID NO:38) or Isovaleric acid-DTHFPCIIFEPRSKGWVCK-NH 2 (SEQ ID NO:128).
15. The method of claim 1 , wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCI(K(PEG8))FGPRSKGWVCK-NH 2 (SEQ ID NO:172) or Isovaleric acid-DTHFPCIKF(K(PEG8))PRSKGWVCK-NH 2 (SEQ ID NO:173).
16. The method of claim 1 , wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCIIFGPRSRGWVC(K(PEG8))—NH 2 (SEQ ID NO:201).
17. The method of claim 1 , wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCI(K(Palm))FGPRSKGWVCK-NH 2 (SEQ ID NO:183).
18. The method of claim 1 , wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCIKF(K(Palm))PRSKGWVCK-NH 2 (SEQ ID NO:217).
19. The method of claim 1 , wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCIKFGP(K(Palm))SKGWVCK-NH 2 (SEQ ID NO:219) or Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(Palm))—NH 2 (SEQ ID NO:221).
20. The method of claim 1 , wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCI(K(PEG3-Palm))FGPRSKGWVCK-NH 2 (SEQ ID NO:222).
21. The method of claim 1 , wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCIKF(K(PEG3-Palm))PRSKGWVCK-NH 2 (SEQ ID NO:223).
22. The method of claim 1 , wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCIKFGP(K(PEG3-Palm))SKGWVCK-NH 2 (SEQ ID NO:224).
23. The method of claim 1 , wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCIKFGPRS(K(PEG3-Palm))GWVCK-NH 2 (SEQ ID NO:225) or Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(PEG3-Palm))—NH 2 (SEQ ID NO:226).
24. The method of claim 1 , wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(PEG8))—NH 2 (SEQ ID NO:176).
25. The method of claim 1 , wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCI(K(isoGlu-Palm))FEPRSKGCK-NH 2 (SEQ ID NO:241).
26. The method of claim 1 , wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCIKF(K(isoGlu-Palm))PRSKGCK-NH 2 (SEQ ID NO:242).
27. The method of claim 1 , wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCIKFEP(K(isoGlu-Palm))SKGCK-NH 2 (SEQ ID NO:243).
28. The method of claim 1 , wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCIKFEPRS(K(isoGlu-Palm))GCK-NH 2 (SEQ ID NO:244).
29. The method of claim 1 , wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCI(K(Dapa-Palm))FEPRSKGCK-NH 2 (SEQ ID NO:248).
30. The method of claim 1 , wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCIKFEP(K(Dapa-Palm))SKGCK-NH 2 (SEQ ID NO:250).Cited by (0)
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